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miRNAs are a class of non-coding RNAs, which bind to the 3'-untranslated regions of their target mRNAs to repress translation. However, the details of miRNA-mediated epigenetic regulation targeting genomic DNA remained largely unknown. Here, we demonstrated that transcription factor CCAAT/enhancer binding protein delta (CEBPD) was responsive to the anticancer drug bortezomib, is a highly selective reversible inhibitor for leukemia treatment, and resulting in caspase activation and apoptosis. Interestingly, following the identification of CEBPD-induced miRNAs, we found that miR-744, miR-3154 and miR-3162 feedback to suppress the transcription of CEBPD itself and genes adjacent to its 5'-flanking region, including protein kinase DNA-activated catalytic polypeptide (PRKDC), minichromosome maintenance-deficient 4 (MCM4) and ubiquitin-conjugating enzyme E2 variant 2 (UBE2V2), upon bortezomib treatment. Additionally, we previously demonstrated that the Yin Yang 1 (YY1)/polycomb group (PcG) protein/DNA methyltransferase (DNMT) complex is important for mediating epigenetic silencing of the CEBPD gene; we further found that Argonaute 2 (Ago2) interacts with YY1 and binds to the CEBPD promoter. Moreover, we revealed that miRNA binding plays a key role for YY1/PcG group protein/DNMT complex-mediated epigenetic gene silencing and is associated with bortezomib-induced methylation on genomic DNA. Altogether, we provided new insights for miRNA-mediated epigenetic regulation in the case of bortezomib-induced cell death in leukemia. Citation Format: Ju-Ming Wang, Yu-Yi Chu, Chiung-Yuan Ko, Shao-Ming Wang, Pin-I Lin, Han-Ying Wang, Wen-Chi Lin, Dong-Yu Wu. miRNAs/Ago2/YY1/PcG protein/DNMT complex mediates epigenetic silencing of locus genes and associates with bortezomib-induced apoptosis of leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 358.

In clinical practice, the main dilemma to a successful ovarian cancer therapy is the development of drug resistance. The mounting evidence demonstrated that microRNAs (miRNAs) not only controlled cell proliferation, invasion and metastasis but also therapeutic resistance of ovarian cancer cell. Recently, we isolated CP70sps(CP70 side population spheres) from CP70 ovarian cancer cell line and proved that CP70sps exhibited more resistant to cisplatin than CP70. This phenomenon was correlated to other study which supported that side population of cancer cells was responsible for chemoresistance. In this study, we compared the expression of miRNAs between CP70sps and CP70 to investigate the role of miRNAs in cisplatin resistance of ovarian cancer cells. Our miRNA array and quantitative RT-PCR data showed that CP70sps expressed lower level of miR-29a/b/c family than CP70 cells and CP70sps4wks cells which were repopulation of CP70sps in attached condition. After knockdown of miR-29a/b/c family by miRNA inhibitors, reduction of miR-29a/b/c family enhanced cisplatin resistance of CP70 cells. However, there was no effect on cell cycle and proliferation rate in both CP70 cells and A2780, a parental cisplatin-sensitive cell line of CP70 cells. Downregulation of miR-29a/b/c family contributed cells to escape cisplatin-induced cell death through COL1A1 upregulation. Moreover, reduction of miR-29a/b/c increased phosphorylation of ERK1/2 and GSK3β to transduce survival signaling and reduced active form casepase-9 to avoid cell apoptosis. Furthermore, we found that either ectopic expression of miR-29 alone or combination of miR-29 with cisplatin treatment efficaciously reduced tumorigenicity of CP70 cells in immunodeficiency mice. Finally, we ascertained that the ovarian cancer patients with high expression of miR-29a had better overall survival rate. Taken together, our data demonstrated that the miR-29 family was a sensitizer for cisplatin treatment and might be associated with tumorigenecity of ovarian cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1110. doi:1538-7445.AM2012-1110

Oncogenic activation of the Wnt/β-catenin signaling pathway is common in hepatocellular carcinoma (HCC). Aberrant hypermethylation of tumor suppressor genes in their promoter regions is frequently found in human cancers. Our previous works have demonstrated that SOX1 gene was hypermethylated in HCCs as well as cervical and ovarian cancers. A growing number of papers suggest that SOX family proteins, such as SOX9, SOX17, SOX4 and SOX2, serve as either tumor suppressors or oncoproteins through manipulating Wnt signaling pathway in different types of cancer. However the molecular mechanism is not well understood. In this study, we established an inducible system to overexpress SOX1 in HCC cell lines and checked whether SOX1 have tumor suppressor function in vitro and in vivo. We found that overexpression of SOX1 could inhibit cell proliferation and colony formation in HCC cells and suppress tumor growth in xenograft mice. Next we used GST pull-down, co-immunoprecipitation (co-IP), immunocytochemistry and luciferase reporter assay to study whether SOX1 could interact with β-catenin to regulate Wnt/β-catenin signaling. Our data showed that SOX1 is physically associated with β-catenin/ TCF complex and could inhibit the TCF-dependent transcriptional activity. Furthermore, SOX1 was co-localized with β-catenin in nucleus by confocal microscopy. These results suggest that SOX1 functions as a tumor suppressor through interfering Wnt/β-catenin signaling in HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2199. doi:10.1158/1538-7445.AM2011-2199